ABSTRACT: The oral fluoropyrimidines have proved to be active in colorectal cancer in Japan and, recently, in the United States and Europe. Continuous oral administration simulates protracted fluorouracil (5-FU) continuous intravenous infusion. The purpose of this trial was to evaluate the tolerability and potential advantages of oral treatment for colorectal cancer in the elderly. The main inclusion criterion was age over 72 years. Patients were treated with UFT (tegafur plus uracil) 400 mg/24 hours (fixed doses) continuously plus folinic acid 45 mg/24 hours until toxicity. If grade 3 or 4 toxicity appeared, treatment was stopped until recovery. From September 1994 to November 1996, 126 patients were included. For the analysis in November 1996, 77 patients were evaluable for response, toxicity, and survival. The patients, including 34 women and 43 men, had a median age of 74 years (range, 72 to 82 years of age). The Karnofsky performance status was 60% to 80% for 41 patients and 90% to 100% for 36 patients. Liver metastasis was present in 48% of the cases, and 42% were locoregional and peritoneal. Toxicity was mild, with only one patient having grade 3 thrombocytopenia, 11 (14%) grade 3 or 4 nausea/vomiting, seven (9%) grade 3 or 4 diarrhea, and one grade 3 mucositis. Four patients (5%) had complete responses and nine (11.6%) partial responses, for an objective response rate of 16.9% (95% confidence interval, 9% to 27%). Twenty-two patients (28.6%) showed no change. The number of patients in whom disease did not progress (ie, patients with complete plus partial responses plus those with stable disease) was 35 (45.4%) (95% confidence interval, 34% to 57%). With a maximum follow-up of 24 months, the median actuarial survival is 14.4 months. The number without disease progression and the median survival in this preliminary analysis suggests that this schedule is a moderately effective, comfortable, treatment with only mild toxicity, that can be recommended for use in the elderly, and it warrants further study.[ONCOLOGY 11(Suppl 10):53-57, 1997]

Introduction

By the year 2000, 70% of cancer cases will occur in patients older than 65 years.[1] Because older patients may not tolerate intensive chemotherapy and because concomitant medical conditions may preclude certain treatments, patients aged 70 years and older may be insufficiently staged and treated.[2] In response to this scenario, we developed a trial to evaluate the tolerability and potential advantages of oral treatment for elderly patients with colorectal cancer using continuous, orally administered folinic acid combined with UFT.

Intravenous modulated bolus fluorouracil-based regimens are the standard treatment for colorectal cancer, with overall response rates ranging from 19% to 23% and median survivals of 10.7 to 11.5 months, according to meta-analyses[3,4], and a response rate of 25.7% and survival of 14.3 months, according to our experience.[5] Several studies in Japan have proved the activity of the oral fluoropyrimidine UFT in colorectal cancer.[6-8] In 1990, Malik et al in Europe achieved a response of 16.6% using UFT alone.[9] Recently, in the United States and Europe, adding folinic acid to UFT has shown good results, yielding 42% and 39% response rates in two studies.[10,11] Continuous-infusion fluorouracil shows good activity against colorectal cancer as well. Using a 48-hour continuous infusion of high-dose fluorouracil (2 to 3.5 g/m2, 48 hours per week), our group has obtained 29% to 38.5% response rates and 12 to 14 months median survival[12-14] in patients with colorectal cancer. The continuous oral administration of UFT is thought to simulate protracted fluorouracil continuous intravenous infusion, making this oral therapy a possible substitute for intravenous chemotherapy.

Patients and Methods

From September 1994 to November 1996, 126 patients entered the study. This data analysis includes 77 patients assessable for toxicity, response, and survival (the other 49 patients were short follow-up). Eligibility criteria included age over 72 years, confirmed colorectal adenocarcinoma, no resectable or metastatic tumor, and measurable disease (ie, at least one lesion measuring 2 x 2 cm at the longest diameter). Eligible patients could not have received prior systemic chemotherapy for metastatic disease. Patients who had received adjuvant therapy were eligible, as long as the therapy was completed at least 6 months before the patient’s inclusion in this study. Karnofsky performance status was required to be at least 60%, and no other malignancies (except basal cell skin cancer or in situ cervical carcinoma) were allowed. Informed consent was required. Laboratory criteria included absolute granulocyte count ³ 1,500/µL, platelets³ 100,000/µL, serum bilirubin£ 1.5 mg/dL, and serum creatinine £ 1.5 mg/dL.

The treatment regimen consisted of UFT 400 mg delivered over 24 hours, in a fixed dose administered orally, twice daily (every 12 hours), plus oral folinic acid 45 mg over 24 hours, in three doses given every 8 hours. Treatment was withheld for grade 3 or 4 toxicity until recovery, when patients resumed treatment at the same doses.

Patient characteristics for the 77 assessable participants are listed in Table 1. Of the 77 patients, 21 had metastatic disease at diagnosis and the disease had relapsed after a disease-free interval (range, 0 to 63 months). The predominant sites of metastasis were liver (48%), and local and peritoneum (42%). The majority of patients (58) had one metastatic site, 16 patients had two, and three patients had three sites.

Response and toxicity were evaluated using standard criteria.[15] Toxicity was evaluated monthly. Response to treatment was evaluated every 2 months by computed tomography scan (chest radiography for lung metastasis was permitted). Only responses of at least 2 months’ duration were considered objective responses. Actuarial median survival was calculated with the Kaplan-Meier method.

Results

Study participants were treated for a median of 4 months (range, 1 to 23); minimum follow-up for these 77 patients was 5 months, to a maximum of 24 months. Toxicity, calculated as the maximum grade for each patient, was mild (Table 2). Only one patient had grade 3 thrombocytopenia; 12 patients (15.6%) experienced grade 3 nausea/vomiting, four (5%) had grade 3 diarrhea, three (4%) had grade 4 diarrhea, and one had grade 3 mucositis. Other toxicities included one case of grade 1 lacrimation and three cases of grade 1 alopecia. Toxicity led to chemotherapy delays in 20 patients (26%), for a median 10-day delay per patient over the treatment period (range, 1 to 48 days). The median UFT dose intensity was 400 mg/d, as planned.

The main objective of our trial was to evaluate the tolerability and potential advantages of oral treatment for colorectal cancer in the elderly. As such, toxicity was mild, necessitating a median of 10 days treatment delay per patient over all months of UFT administration. When diarrhea appeared, it was easily controlled by loperamide (Imodium). The overall response rate of 16.8% is low, but it is in the range found in the meta-analyses of randomized trials using either fluorouracil modulated by folinic acid[3] or fluorouracil with methotrexate.[4] Compared with the results in the Pazdur et al[10] and Gonzalez-Barón et al[11] trials, however, our results are substantially worse in terms of response rate.

However, it should be noted that the studies were not comparable with respect to dose intensities: The dose intensity in our study (UFT fixed dose, 400 mg/d), yielded 7,500 mg/m2/month over a body surface area of 1.6 m2 to 6,650 mg/m2 for a body surface area of 1.8 m2. The dose intensity used by Pazdur and colleagues (300 mg/m2/day x 28 days) yielded 8,400 mg/m2/month.[10] In the Gonzalez-Barón trial, a dose intensity of 390 mg/m2/day x 14 days led to a total of 5,460 mg/m2/month.[11] Our trial, however, employed an intermediate dose, and dose is therefore likely not the reason for our lower response rate.

The main difference between the present study and the other two is the distribution of metastases. Liver metastasis is related to a higher response rate in most of the studies. Only 48% of our patients had liver metastases, a lower percentage than in the studies mentioned above, and 42% had less responsive local and peritoneal metastasis. Moreover, the locoregional and peritoneal masses present fibrous and irregular areas, which makes their evaluation by computed tomography scan difficult and increases the number of patients with stable disease. Among patients with nonprogressing disease, including patients with stable disease (CR + PR + SD), a 45% response rate was achieved (95% confidence interval, 34% to 57%). Patients with stable disease represent a sizable number of cases of colorectal cancer. Their prognosis is similar to that of patients achieving objective responses, in regard to progression and survival. We saw no difference in survival between these two patient groups. Overall survival was very good–-14.4 months median survival–-similar to that obtained by our group using high-dose continuous-infusion fluorouracil.[10-12]

Conclusion

The combination of UFT and folinic acid in low-dose continuous oral administration is a comfortable treatment for elderly patients with colorectal cancer. This regimen appears to be moderately effective in this population with only mild toxicity, and it warrants further study.